Risdiplam distributes and increases SMN protein in both the central nervous system and peripheral organs

Research Highlights Life Science

SMN: a biomarker to assess treatment efficacy for Spinal Muscular Atrophy

Expert opinion

SMN1-related proximal spinal muscular atrophy (or SMA) is rare, but it is the second leading cause of childhood neuromuscular diseases. Abnormality (absence or mutation) of SMN1 gene coding for protein results in the absence of the SMN1 protein that impairs survival of motoneurons and causes their degeneration. This results in muscular paralysis with symptoms that vary from one form to another, depending on the age of onset in patients. SMN2, a closely related protein, can partially compensate SMN1 functions. The SMN2 gene is capable of producing half of a normal SMN protein and half of a shortened non-functional protein. The number of copies of the SMN2 gene varies from one individual to another. Appropriate treatments depending on patient profiles need to be identified and provided.
There is no optimal cure for SMA and there is no known way to prevent it, as it is an inherited genetic disease. In December 2016, the U.S. Food and Drug Administration (FDA) approved a drug called nusinersen (Spinraza) to treat SMA. This is the first drug to be approved for the disorder. Other emerging treatments are in preclinical or clinical stages. Risdiplam (RG7916 or RO7034067) is a compound that modulates the maturation and processing of SMN2 mRNA. Reintegration of the missing exon 7 through mRNA splicing promotes protein synthesis rescue in SMN deficient patients.
In this article, Agnès Poirier designed a set of pre-clinical studies in animals (mice, rats, and cynomolgus) to study the bioavailability of Risdiplam (PK studies) thoroughly. The efficacy of Risdiplam, delivered at different doses, was highly correlated to the level of SMN proteins. A reliable and straightforward assay to quantify SMN1 extracted from different tissues (brain, muscle, bone marrow, heart, liver, kidney, and spleen) was a key asset in her preclinical investigations.
It looks like this new treatment to cure SMA has found its biomarker. Use it also to monitor and follow-up on the efficacy of your own compound candidates


Spinal muscular atrophy (SMA) is a rare, inherited neuromuscular disease caused by deletion and/or mutation of the Survival of Motor Neuron 1 (SMN1) gene. A second gene, SMN2, produces low levels of functional SMN protein that are insufficient to fully compensate for the lack of SMN1. Risdiplam (RG7916; RO7034067) is an orally administered, small-molecule SMN2 pre-mRNA splicing modifier that distributes into the central nervous system (CNS) and peripheral tissues. To further explore risdiplam distribution, we assessed in vitro characteristics and in vivo drug levels and effect of risdiplam on SMN protein expression in different tissues in animal models. Total drug levels were similar in plasma, muscle, and brain of mice (n = 90), rats (n = 148), and monkeys (n = 24). As expected mechanistically based on its high passive permeability and not being a human multidrug resistance protein 1 substrate, risdiplam CSF levels reflected free compound concentration in plasma in monkeys. Tissue distribution remained unchanged when monkeys received risdiplam once daily for 39 weeks. A parallel dose-dependent increase in SMN protein levels was seen in CNS and peripheral tissues in two SMA mouse models dosed with risdiplam. These in vitro and in vivo preclinical data strongly suggest that functional SMN protein increases seen in patients’ blood following risdiplam treatment should reflect similar increases in functional SMN protein in the CNS, muscle, and other peripheral tissues.


Pharmacology Research & Perspective. 2018 Nov 29;6(6): e00447.

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